DESIGN AND EVALUATION OF CARBAMAZEPINE LOZENGES

Objectives: Carbamazepine (CBZ) is an anticonvulsant drug used in the treatment of epilepsy and neuropathic pain. The aim of present study was to develop and evaluate lozenges of Carbamazepine for improvement of bioavailability and patient compliance especially for those patients who have difficulty in swallowing Methods: The lozenges were prepared using sucrose as base; HPMC K4M, methyl cellulose were used as polymers by heating and congealing method on laboratory scale. All the formulations prepared were subjected to various physicochemical parameters like hardness, friability, weight variation, drug content and in vitro dissolution studies. Stability studies of selected formulations of batch CL4 were also carried out at 40/75% relative humidity for 6 months. Results: All the formulations showed good physical appearance. The Thickness of the formulations was in the range of 14.23±0.12 to 14.50±0.06cm, weight variation was found to be in the range of 2.34± 0.12 to 4.51± 0.08%. The percent drug release was found in the range of 55.49 to 93.27%. Selective formulation was found to be stable at different temperature conditions. Conclusion: Study concludes that incorporating polymers like HPMC K4M and methylcellulose can be used to formulate effective medicated Carbamazepine lozenges especially for patients who cannot swallow solid oral dosage forms


INTRODUCTION
The word "Lozenge" is derived from French word "Losenge" which indicates a diamond shaped geometry with four equal sides 1 . Lozenges are the flavored medicated solid, unit dosage forms intended to be sucked and held in the mouth or pharynx containing one or more medicaments usually in the sweetened base 2 . They dissolve slowly in the mouth and so release the drug dissolved in the saliva. The drugs having a large dose can be easily administered formulating as lozenges. The oral route of drug administration is most preferred route because of many advantages associated with it like ease of ingestion, pain avoidance, versatility and most important patient compliance 3 . However geriatric and pediatric patients suffer from dysphagia (difficulty in swallowing), thus oral route for drug administration is not suitable in these cases. There are other conditions in which oral route is not preferred like unavailability of water, sudden episodes of allergic attack, mentally retarded patients 4 . Most of the lozenge preparations are available as over the counter medications. The dosage form can be adopted for local as well as systemic therapy and a wide range of drugs like analgesics, anesthetics, antimicrobials, antiseptics, antitussives, aromatics, astringents, corticosteroids, decongestants, demulcents and other can be delivered in the form of lozenges 5 . Lozenges are associated with many advantages like avoidance of first pass hepatic metabolism, no need of water intake, reduction in gastric irritation, improved bioavailability with reduced dosing frequency to minimum side effects 6 . Carbamazepine (CBZ) is an anticonvulsant is a medication used primarily in the treatment of epilepsy and neuropathic pain 7 . It is used in schizophrenia along with other medications and as a second line agent in bipolar disorder. Carbamazepine is relatively slowly but well absorbed after oral administration 8 . Its plasma half-life is about 30 hours when it is given as single dose, but it is a strong inducer of hepatic enzymes and the plasma half-life shortens to about 15 hours when it is given repeatedly. It is highly lipophilic with an aqueous solubility of 0.078 mg/l. After oral administration it has poor bioavailability of 42-58%. It is a bitter drug with an unpleasant aftertaste 9 . In present study lozenges of Carbamazepine were prepared in order to improve bioavailability and increase patient compliance.

MATERIALS AND METHODS
Carbamazepine was obtained from Reals Pharmaceuticals Limited, Lagos, Nigeria. Eudragit E 100, methyl cellulose, Polyethylene glycol 8000 and HPMC K4M were obtained from AC drugs ltd (Enugu, Nigeria). Sucrose and dextrose were provided by McNichols Plc, Ogun State, Nigeria. Citric acid was obtained from Mekz Global Limited (Lagos) Preparation of Carbamazepine lozenges Carbamazepine lozenges were prepared in laboratory scale by heating and congealing technique, the composition as given in table 1. Required quantity of all ingredients were transferred into a copper bowl, and then heated in a heating mantle at 150°C for 15 minutes. Then the temperature of the mixture was brought into 90°C, then Carbamazepine, polymers, flavoring agent and coloring agent were added with stirring by using glass rod, and the solution was transferred into a lubricated mould. It was allowed to cool for solidification then lozenges were collected and packed in an aluminum foil 10 .

Weight variation
The formulated Carbamazepine lozenges were tested for weight uniformity. Twenty formulations were collectively and individually weighed. From the collective weight, average weight was calculated. Each lozenge weight was then compared with average weight to ascertain whether it is within permissible limits or not 12 .

Hardness
The lozenge crushing strength, which is the force required to break the lozenge by compression in the diametric direction. The hardness of the Carbamazepine lozenges was determined by using Monsanto Hardness tester, where the force required to break the lozenges was noted. It is expressed in kg/cm 2 .
Ten formulations of each batch were used for the estimation of hardness 13 .

Friability
The Roche friability test apparatus was used to determine the friability of the lozenges. Six pre weighed Carbamazepine lozenges were placed in the apparatus, for 4 min at 25 rpm. Then the lozenges were reweighed. The percentage friability was calculated by using the formula 14 .

Drug content
Three Carbamazepine lozenges from each batch were selected and weighed individually and crushed in a mortar. Drug was extracted with 100 ml of distilled water. The drug content was determined spectrophotometrically at 285 nm with blank lozenge extract as the reference. The formulated lozenges were evaluated for the following parameters 15 .

In vitro dissolution studies
In vitro dissolution studies of Carbamazepine lozenges were carried out in 900 ml phosphate buffer pH6.8 using USP dissolution testing apparatus with a rotating stirrer speed at 100 rpm, and temperature of dissolution medium maintained at 37±0.5°C. The rpm of the paddle was fixed at 100. Aliquots of 5ml were withdrawn at regular intervals; filtered and same amount of fresh dissolution medium was replaced at the same temperature. The filtered solutions were analyzed by using (Shimadzu, Japan) UVspectrophotometer at 285 nm 16 .

Disintegration test
The disintegration time of Carbamazepine lozenges were determined by USP Disintegration apparatus and disintegration time was noted in buffer of pH 6.4 at 37 o C 17 .

Stability test
For accelerated stability study, selected formulation was kept in airtight dark container according to ICH guidelines at 40/75% relative humidity for 6 months 18 .

RESULTS AND DISCUSSION
Four different formulations of Carbamazepine lozenges were prepared successfully in laboratory scale by heating and congealing technique. Different ingredients i.e. Eudragit E 100, HPMC K4M, sucrose, dextrose, polyethylene glycol 8000, methylcellulose, citric acid, aspartame, talc, coloring agent, menthol were incorporated in different ratio. In the Carbamazepine lozenges formulations menthol was used as flavoring agent, it provides a desirable soothing effect.    figure 1.The percent drug release was found in the range of 55.49 to 93.27%. Carbamazepine lozenges formulations of batch CL4 showed a release of 93.27% in 30 minutes, which was relatively faster in comparison to the other formulations prepared from ordered mixture, which may be due to the presence of Polyethylene glycol 8000, which aid in faster disintegration of the prepared lozenges. Since methylcellulose is a hydrophilic polymer, it facilitates quick release of drug. But as the concentration crosses the optimum quantity it retards drug release 15 . During stability study of 6 months of selected Carbamazepine lozenges formulations of batch CL4, it was observed that the concentrations of drug in all the formulations were decreased a bit, within the pharmacopoeia limits. It was found that there was a slight change in taste and color of all the lozenges. Hence in the stability studies carried for six months it was found that there wasn't any substantial changes in hardness, friability, weight uniformity, % drug content, disintegration time the selected formulations were stable throughout the study. Lozenges enjoy an important position in pharmacy and will continue to remain at the same in future. From present study it is concluded that incorporating polymers like HPMC K4M and methylcellulose can be used to formulate effective medicated Carbamazepine lozenges especially for patients who cannot swallow solid oral dosage forms like tablet and capsules. This will offer better patient compliance and innovative dosage form. Lozenges are intended to slowly dissolve in the mouth over a relatively long period of time usually about 2-15 min or more as needed. By incorporation of synthetic polymers yields good results and release the drugs for a prolonged period of 30 min. Based on different parameters Carbamazepine lozenges formulations of batch CL4 can be considered as the optimized formulation.

AUTHOR'S CONTRIBUTION
The manuscript was carried out, written, and approved in collaboration with all authors.